Compositions Containing Enriched Natural Crocin and/or Crocetin, and Their Therapeutic or Nutraceutical Uses

ABSTRACT

The invention relates to unique compositions containing enriched and purified natural crocin and/or crocetin for prevention and/or treatment of cancers and other conditions and diseases. Compositions comprise mainly enriched or purified natural crocin or crocetin or combination of both and possible other active phytochemicals. A composition is used as functional food, drink, dietary supplement, or therapeutic dosage to a human orally or through other appropriate way (parenteral, percutaneous, rectal, mucosal, intranasal or topical administration). A method of natural crocin and crocetin enriching and purification is revealed.

CROSS-REFERENCE TO EARLIER FILED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/727,244, filed Nov. 16, 2012, the entire content of which is herebyincorporated by reference in this application.

FIELD OF THE INVENTION

The subject application relates to compositions containing enriched orpurified natural crocin and/or crocetin for enhancing health andpreventing or treating cancers and other diseases and health conditions.

BACKGROUND OF THE INVENTION

Cancer is the leading cause of death in the world population. In 2008,there were an estimated 12.7 million new cancer cases diagnosed and 7.6million deaths from cancer around the world according to <<Global CancerFacts & Figures 2nd Edition>>. American Cancer Society estimates in 2012over 1.6 million new cancer cases and about 577,000 deaths resulted fromcancer in the United States in “Cancer Facts & Figures 2012”. By 2030,the global burden is expected to grow to 21.4 million new cancer casesand 13.2 million cancer deaths. Although there are a few promisingoptions for cancer prevention, treatment mainly involves surgicalremoval of tumor or cancer and surrounding tissue plus chemotherapy andradiotherapy or chemotherapy alone or in combination with radiationwithout surgery. Various new drugs were developed for specific cancer inchemotherapy. Most often, chemotherapy is limited by severe side effectsand dose limiting toxicity. Not only these chemotherapy caused sideeffects worsen patients' quality of life, but it can also result instopping potentially curative treatment. So far, it still is a greatchallenge to find effective treatment with no/low adverse effects.

Increasing number of cancer patients uses plants, vegetables, herbs, andspices or its derived products as traditional medicine or alternativemedicine. At least half of cancer patients in the United States usecomplementary and alternative medicine, exclusively or concurrently withtraditional therapeutic regime such as radiation therapy and/orchemotherapy. It is ideal to develop drug or treatment from in fruits,vegetables, herbs and spices that are efficacious and without adverseside effect. Most preferably, a product or products can be invented toprevent development of various cancers and other diseases. Thisinvention relates to improvements in human nutrition and therapeuticsinvolving providing unique compositions with enriched or purifiednatural crocin and crocetin and/or other phytochemicals constitutinganti-cancer compositions which can prevent, reduce and treat cancer aswell as prevent or treat other diseases and conditions, includingage-related and neurodegenerative disorders such as Alzheimer's andParkinson's diseases, cardiovascular and cerebrovascular disease,digestive system diseases, toxin and alcohol caused liver injuries. Thecompositions can be used alone against cancer and protect normal cellsand organs, or used in combination with other chemotherapy in asynergistic fashion that serve as sensitizer to more effectively killabnormal cells while protect normal cells and organs at lower chemodose, or in combination with radiotherapy against cancers and protectnormal cells and organs undergoing radiation.

Crocin and crocetin exist in Crocus. They are the chemical componentswith antioxidative properties primarily responsible for the color of thestigmas of Crocus sativus L. (Saffron). Crocetin is a carotenoiddicarboxylic acid with 20 carbon atoms and it is the core of crocin.Crocin, in general term, includes Crocin-I(Crocetin-di-beta-D-gentiobiosyl ester), Crocin-II(Crocetin-beta-D-gentiobiosyl-beta-D-glucosyl ester), Crocin-III(Crocetin-mono-beta-D-gentiobiosyl ester), Crocin-IV(beta-D-monoglucoside ester of monomethyl alpha-crocetin),Crocetin-di-(beta-D-glucosyl) ester, Crocetin-mono-beta-D-glucosylester. Crocin mainly exists in trans-form, but can also present incis-form in minor amount.

To demonstrate a few, chemical structure of crocetin (alpha-crocetin) isshown below:

Chemical structure of Crocin-I (Crocetin-di-beta-D-gentiobiosyl ester)is shown below:

Chemical structure of Crocin-II(Crocetin-beta-D-gentiobiosyl-beta-D-glucosyl ester) is provided below:

Chemical structure of Crocin-III (Crocetin-mono-beta-D-gentiobiosylester) is shown below:

Saffron is used as coloring and flavoring agents in the preparation offood in different parts of the world and has been used since ancienttimes for strengthening digestion, relieving coughs, smoothingmenstruation, relaxing muscle spasms, improving mood, calming anxiety,preventing depression and enhancing men's sexual ability. Saffron isalso used as health tonic. It is believed that regular intake of saffronwith milk helps to build resistance against common cold and asthma. Inrecent years, Saffron is reported to possess anti-oxidant andanti-cancer effects among a wide range of pharmacological activities(Abdullaev F I. 2002, Chermahini S H. 2010, and Bhargavak V. 2011).

Commercial saffron is produced in Azerbaijan, France, Greece, India,Iran, Italy, Spain, China, Israel, Morocco, Turkey, Egypt, and Mexicofrom dried stigmas of cultivated Crocus sativus L. Each flower has onlythree small stigmas. It takes about 75,000 flowers to produce one poundof saffron. Currently, Saffron is produced worldwide at an annual rateof about 300 tons and harvested by hand, making Saffron an extremelyexpensive commodity with very limited supply. Saffron is safe to use.Saffron and saffron extracts have been safely used as spice, foodcoloring or for medicinal purposes for hundreds of years. Saffron isregarded as a food by Joint FAO/WHO Expert Committee on Food Additives(TRS 733-JECFA 29/33) and listed as substance Generally Recognized AsSafe (GRAS) by FDA [CITE: 21CFR182.10, Revised as of Apr. 1, 2012].

Another source of crocin and crocetin is the gardenia fruit, Gardeniajasminoides Ellis or Gardenia augusta Merrill var. grandiflora Hort.Content of crocin in gardenia fruits increases when ripening. Gardeniafruits have been used in China and Japan as traditional medicine for itsantiphlogistic, diuretic, and cholagogic effects. Gardenia fruit islisted and approved in 1998 by Chinese government both as food and asmedicine and listed in The Japanese Pharmacopoeia as crude drug and inthe list of existing food additives (Yoshiaki Kato 2000). Its extract,gardenia yellow, has also been listed as INS. 164 by JECFA (1989) as afood additive for colorant and widely used to give yellow color to foodproducts such as noodle, pasta, candy, beverage and pickled products inJapan. Gardenia yellow has almost the same crocin and crocetinderivatives as saffron, only different in composition ratio of crocinand crocetin derivatives (Carmona M. 2006, Chen Y. & Zhang H.2008).

Studies have shown saffron extracts have anti-cancer activities. Theanticancer/antitumor properties of crude extracts of saffron have beendemonstrated in vitro and in vivo (Nair S C 1991, 1994, Abdullaev F I.2002, 2003, Chryssanthi D G. 2007, Bakshi H. 2010). Crocin in saffroncauses apoptosis in different type cancer cells. It is of great interestthat non-tumor cells in culture appear to be insensitive to the effectsof such extracts compared with tumor cells. Even saffron extract wasfound to stimulate or support in vivo growth of normal human lung cells(Abdullaev F I, 1992a,b).

Saffron aqueous extract rich in crocin was found protect animal againstgenetic damage induced by anti-cancer agents (Premkumar K. 2006). Inthis study, to ascertain the chemoprotective potential of saffronagainst the genotoxicity of three well-known anti-tumor drugs-cisplatin(CIS), cyclophosphamide (CPH) and mitomycin C (MMC)-using comet assay,Three doses of saffron (20, 40 and 80 mg/kg b.w.) were orallyadministered to mice for five consecutive days prior to theadministration of anti-tumor drugs under investigation. Pre-treatmentwith saffron significantly inhibited anti-tumor drugs induced cellularDNA damage (strand breaks) as revealed by decreased comet tail length,tail moment and percent DNA in the tail.

Formation of toxic amyloid structures is believed to be associated withvarious late-onset neurodegenerative disorders such as Alzheimer's andParkinson's diseases. One human study (Akhondzadeh 2010) was carried outto investigate saffron may inhibit the aggregation and deposition ofamyloid 0 in the human brain and may therefore be useful in Alzheimer'sdisease (AD). Fifty four patients were screened for a 22-week,double-blind study of parallel groups of patients with mild to moderateAD. The psychometric measures, which included AD assessmentscale-cognitive subscale (ADAS-cog), and clinical dementia ratingscale-sums of boxes, were performed to monitor the global cognitive andclinical profiles of the patients. Patients were randomly assigned toreceive capsule saffron 30 mg/day (15 mg twice per day) (Group A) ordonepezil 10 mg/day (5 mg twice per day) for a 22-week study. Saffron atthis dose was found to be effective similar to donepezil in thetreatment of mild-to-moderate AD after 22 weeks, while the donepezilgroup experienced significant frequency of vomiting.

Alcohols or ethanol over consumption is known to impair learning andmemory. The acute effects of an alcohol extract of Crocus sativus L(saffron) were studied on learning and memory in step through and stepdown tests in normal as well as in learning- and memory-impaired mice(Zhang 1994). Saffron extract reduced the ethanol-induced impairment ofmemory registration both in step through and step down tests and theethanol-induced impairment of memory retrieval in step down test.Saffron extract decreased the motor activity and prolonged the sleepingtime induced by hexobarbital. It was suggested that saffron extractameliorates the impairment effects of ethanol on learning and memoryprocesses, and possesses a sedative effect. In behavioral andelectrophysiological studies (Abe K. 2000), Saffron extract improvedethanol-induced impairments of learning behaviors in mice, and preventedethanol-induced inhibition of hippocampal long-term potentiation, a formof activity-dependent synaptic plasticity that may underly learning andmemory. This beneficial effect of saffron extract is attributed tocrocin (crocetin di-gentiobiose ester), but not crocetin. It wasindicated that Saffron extract or its active constituents, crocetin andcrocin, could be useful as a treatment for neurodegenerative disordersaccompanying memory impairment.

Dietary saffron was found in animal study (Maccarone R. 2008) maintainsmorphology and function after exposure to damaging light in mammalianretina. The photoreceptor layer was largely preserved in saffron-treatedanimals. Rate of photoreceptor death induced by the damaging brightcontinuous light drastically reduced in saffron treated animals. Saffronsupplement was found to improve retinal flicker sensitivity in earlyage-related macular degeneration (AMD) (Falsini B. 2010). Followed upclinical study in Italy and Australia supported saffron supplementationand indicated crocin and crocetin as key actives to provide sustainedbenefits to central retinal function for AMD patients (Piccardi M. 2012)

Though saffron is reported to possess anti-oxidant and anti-cancereffects among a wide range of pharmacological activities, it is thesemain components, crocin and crocetin that were indicated to providethese pharmacological activities. Due to the very limited source andexpensiveness of saffron, it is unrealistic to produce large scale ofhighly enriched crocin and crocetin from saffron. Saffron quality andits content of crocin and crocetin vary significantly, range from lessthan 1% to 20% (Alonso G L. 2001, Lechtenberg M. 2008). Quantificationstudy of saffron also indicated a high amount of adulterant on thesaffron market (Lechtenberg M. 2008). Chemically synthesized crocetinand its salts are not natural and not identical to natural crocin andcrocetin, and may possess very different biologically andpharmacologically properties. Gardenia fruits, gardenia extracts, orgardenia yellow provide a feasible source to enrich and purifyindustrial scale of natural and high purity crocin and/or crocetin forwide applications. Enrich and purified crocin and/or crocetin rendermeans to quantitatively and consistently deliver the actives informulated products for preventing and treating cancers and otherdiseases.

Many other phytochemicals (organic chemicals from plant source) alsohave extensive and variety of health benefits in preventing or treatingdiseases or cancers. A few examples are provided here. Resveratrol ingrape has been studied and reported to have anti-cancer effects,anti-inflammatory effects, cardiovascular benefits, anti-diabetespotential, energy endurance enhancement, and protection againstAlzheimer's (Baur J A 2006). Curcuminoids, include curcumin,demethoxycurcumin, and bisdemethoxycurcumin, are polyphenolic pigmentsfound in the spice turmeric. Curcumin has been widely studied andindicated to have anticancer, anti-inflammatory, antiviral,hypocholestrolemic and break-up of beta-amyloid plaques in brainactivities (Aggarwal B B. 2007). Tea polyphenols, including catechin,epicatechin, epicatechin gallate, epigallocatechin, epigallocatechingallate, theaflavin, theaflavin-3,3′-digallate, theaflavin-3-gallate,etc. and extracts have also been studied and showed extensive healthbenefits including anticancer, cholesterol-lowing, anti-inflammatory,anti-aging, and against atherosclerosis and coronary heart disease, highblood cholesterol concentrations, and high blood pressure (Mukhtar H.2000). Anthocyanins are a category of phytochemicals in fruits andvegetables that give them vivid red to blue. Based upon many cell-linestudies, animal models, and human clinical trials, Anthocyanins havebeen suggested possess anti-inflammatory and anti-carcinogenic activity,cardiovascular disease prevention, obesity control, diabetesalleviation, and eye health promoting properties (He J 2010, Kalt W2010). Human studies with diet rich in anthocyanins suggest it may alsoprotect against development of Parkinson's disease and improve bloodpressure (Cassidy J. 2011, Gao X. 2012).

Prior arts have been mostly focused on purify shingle crocin component,either crocin-1 (alpha-crocin) or crocetin. CN102516325 A revealed amethod of producing crocin with higher than 95% purity from gardenia.The prior art specifically produces one single crocin component, crocinI (called crocin in prior art) to purity at least 95%. WO2004078695 A1revealed a method for purification of crocetin. Method in this prior artincludes steps of hydrolysis of crocin and then purification ofcrocetin. Prior arts also include methods of extracting, changingprofile of crocin and crocetin or improving recovery of saffron colorantrecovery. WO2010094745 A1 and US2010/0210572A1 revealed a method ofproducing hydrolysate of crocin, resulting in crocin related productswith significant amount of crocetin mono esters. WO2004056201A1 revealeda method of increased colorant (crocin and crocetin) recovery fromsaffron raw material to 95%, while crocin and crocetin together having apigment concentration of 15-24%. Crocetin and its salts have beenchemically synthesized (WO2006104610 A2, US7351844 B2). But thesechemically synthesized crocetin and its salts are not natural and maynot have the same biological and pharmacological properties.US20130156746 A1 revealed a dietary supplement composition whichcomprises saffron powder and resveratrol. Because saffron has manydifferent grades and varies in its crocin content, it is very difficultto use such a composition for products require quality and efficacyconsistency. US20110236481 A1 revealed a composition contains safranaland/or crocin and/or picrocrocin from saffron plant or saffron assatiety agent for treatment of obesity. The active contents of safranaland/or crocin and/or picrocrocin are used at low or diluted level byweight compare to saffron in products and showed to be effective insuppressing hungry (Gout B. 2010).

Applications of enriched and purified natural crocin and/or crocetinenable quality consistency and quantitative amount of crocin and/orcrocetin in products. Its use alone or use in combination with otherhealth beneficial phytochemicals in nutraceutical or therapeuticcomposition is useful in preventing and treating many cancers anddisease as well as enhancing health. Combinations of crocin and/orcrocetin with other phytochemicals also offer synergistic and broaderbenefits in preventing and treating cancers and diseases. The inventionis focused on crocin and/or crocetin that are extracted, enriched orpurified from natural source, gardenia fruits, gardenia extracts orgardenia yellow, to formation unique nutraceutical or pharmaceuticalcompositions with or without other health promoting phytochemicals, andtheir uses for (a) prevention or treatment of diseases and conditionsincluding cancers, neurodegenerative diseases, heart diseases, liverdiseases, kidney diseases, eye diseases, metabolic syndrome,atherosclerosis, arthritis, inflammations, obesity, or diabetes, etc.;(b) protection of liver, heart, kidney, and other normal organs frominjuries or damages; (c) improvement or enhancement of learning/memoryability, immune system, skin health, anti-aging, and over all health.

SUMMARY OF THE INVENTION

Saffron provides many health benefits and has been safely used forthousand years, but quality of saffron and the content of key actives,crocin and crocetin, vary significantly. Enriched and purified naturalcrocin and/or crocetin of this invention reduce or eliminate undesirablecomponents in saffron or gardenia fruits. It provides means to deliverquantitatively and consistently effective amount of crocin and/crocetinin compositions or formulated products for preventing and/or treatingcancers and other diseases as well as enhancing and improving health.High purity crocin and/or crocetin is particular advantageous in acomposition for injectable products.

It is an object of the invention to provide compositions and a means forimproving/enhancing cancer prevention, treatment and reducing cancerrisk as well as improving other conditions and diseases.

It is an object of the invention to provide compositions and a means forimproving/enhancing/restore cells, tissues, and organ functions ofcancer suffer patients. Improve and prolong life span.

It is an object of the invention to provide compositions and a means forimproving/enhancing therapeutical effectiveness of other cancer drugsthrough synergistic effects or as sensitizer or enhancer, reducing drugresistance.

It is an objective of the invention to provide compositions and a meansfor improving/protecting non-cancerous or normal cells, tissues, organsand patients from injury, damage by other anti-cancer agents, toxins,chemotherapeutic agents, radiation.

It is an object of the invention to provide compositions and a means forimproving/enhancing healthy aging and mental health, particularlyresponses in central nerve system that slow, prevent, and mitigateneurodegenerative disorders such as Alzheimer's and Parkinson'sdiseases; inhibit producing neurotoxins, inhibit acetylcholinebreakdown, prevent formation of toxic amyloid structures; enhance brainfunction, have an effect of improved quality of life.

It is an object of the invention to provide compositions and a means forimproving/enhancing learning and memory and cognitive abilities; reduceoxidative stress damage to the hippocampus induced by chronic stress.

It is an object of the invention to provide compositions and a means forimproving/treating ethanol/alcohol-induced impairments of learning andmemory and cognitive abilities; improve/treat neurodegenerativedisorders accompanying memory impairment.

It is an object of the invention to provide compositions and a means forprotecting/improving/enhancing heart function/structure/composition,particularly responses that improve cardiac arrhythmia and antioxidantsystems, prevent the myocardial infarction and relieve myocardialstunning; improve/enhance recovery of heart function.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses that reducechronic inflammation and prevent inflammatory conditions; providetreatments that will be simple and effective and will have little or noadverse side effects.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses that improveand enhance immune system and, thereby, having an effect ofregulating/boosting the health of human.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses that treat andreduce serum triglyceride, total cholesterol, low density lipoprotein(LDL) cholesterol and very low density lipoprotein (VLDL) cholesterollevel.

It is an object of the invention to provide compositions and a means forimproving/enhancing liver function/activities, particularly responsesthat protect, prevent liver injury from alcohols, toxins, metal or heavymetal over dose; protect liver from chemo agent injury and damage.Maintain and enhance recovery of liver function.

It is an object of the invention to provide compositions and a means forimproving/enhancing liver health, particularly responses thatimprove/enhance liver recovery from injury and shock, thereby, having aneffect of maintaining/boosting health of human.

It is an object of the invention to provide compositions and a means forimproving/enhancing kidney function/activities, particularly responsesthat protect, prevent kidney injury and damage; maintain and enhancerecovery of kidney function.

It is an object of the invention to provide compositions and a means forimproving/enhancing eye health, particularly responses thatslow/prevent/treat age related macular degeneration; increase blood flowto the retina and choroid, also facilitate retinal function recoverythereby preventing ischemic retinopathy and age related maculardegeneration.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses that improvediabetic benefits, inhibit insulin resistance or insensitivity inducedby fat or various fatty acids or high sugar diets; restore/maintainnormal pancreatic functions/orders, prevent glucose toxicity.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses thatprevent/treat obese and associated diseases/conditions.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses thatreduce/prevent/treat atherosclerosis, thereby, having an effect ofregulating/boosting the cardiovascular health and lowering cholesterol;prevent/treat coronary artery disease and peripheral vascular disease.

It is an object of the invention to provide compositions and a means forimproving/enhancing human health, particularly responses that improvesense of well-being and, thereby, having an effect of calming,prevent/improve depression.

It is an object of the invention to provide compositions and a means forimproving/enhancing skin health and appearance, particularly responsesthat improve skin conditions in anti-aging, anti-wrinkle,anti-inflammation, anti-oxidation, restore/prevent/treat skin damage andthe signs of aging of the skin.

It is an object of the invention to provide specific combinations ofingredients or formula containing enriched or purified natural crocinand/or crocetin that deliver bioactive components which directly,effectively prevent/treat/benefit cancer/tumor patients.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated to enhance bio-actives intakes.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to effectively prevent/protect risk of cancers, treat/benefitcancer/tumor patients.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to improve/protect non-cancerous or normal cells, tissues,organs and patients from injury/damage by other anti-cancer agents,toxins, chemotherapeutic agents, radiation.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to effectively prevent/treat/benefit neurodegenerationpatients; prevent/slow/treat Alzheimer's and Parkinson's diseases.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to effectively prevent/treat/benefit patients with impairmentin learning and memory; improve/enhance learning and memory.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to effectively enhance/improve heart health, treat individualswith heart illness or sub-normal conditions.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to effectively inhibit inflammations, chronic inflammationswhich may lead time many health problems.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to enhance/improve immune system.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to enhance/improve human circulation system, lower cholesterol,triglyceride and low density lipoprotein.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to enhance/improve liver health, protect/prevent liverinjury/damage from alcohol/ethanol, toxins, chemotherapeutic agent.Strengthen/restore liver functions.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to effectively enhance/improve eye health, prevent/slow/treatindividuals with age-related illness or sub-normal conditions.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to enhance and benefit individuals with diabetes.

It is another object of one aspect of the invention to provideimprovements of human nutrition by the combinations, in particularspecially formulated with enriched or purified natural crocin and/orcrocetin to enhance and benefit individuals with coronary artery diseaseand peripheral vascular disease; to prevent and reduce risk of coronaryartery disease and peripheral vascular disease.

These and other objects are achieved by the invention, which providesfood/dietary/therapeutic compositions/formula comprising uniquecombinations of enriched or purified natural crocin and/or crocetin andregimens employing them to enhance and maintain health and improvesub-health conditions.

These and other objects are achieved by the invention, which providestherapeutic compositions/formula comprising unique combinations ofenriched or purified natural crocin or crocetin alone or both incombination with other excipient or stabilizer to prevent or treatcancers/tumors.

These and other objects are achieved by the invention, which providesfood/dietary/therapeutic compositions comprising unique combinations ofnatural enriched crocin and crocetin and possible other bio-actives,proteins, peptides and amino acids constituting immune system improvingnutraceutical compositions and regimens employing them to reduce risksin individuals with suppressed/abnormal immune systems.

These and other objects are achieved by the invention, which providesfood/dietary/therapeutic compositions comprising unique combinations ofnatural enriched crocin and crocetin and possible other bio-actives,vitamins constituting antioxidant nutraceutical compositions andregimens employing them to reduce risks of diseases

These and other objects are achieved by the invention, which providesfood/dietary/therapeutic/topical compositions comprising uniquecombinations of natural enriched crocin and crocetin and possible otherbio-actives, constituting antioxidant nutraceutical compositions andregimens employing them to reduce risks of radical damages, chemicaldamages and photo-damages to normal cells, tissues, organs, (liver,skin, etc.).

It is also an objective of this invention to provide a method to enrichor purify crocin and/or crocetin from gardenia fruit, gardenia extract,gardenia yellow, or saffron.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the flow diagram of crocin enriching and purification fromgardenia yellow D500 as described in Example 1.

FIG. 2 shows HPLC chromatograms of crocin obtained as described inExample 2.

FIG. 3 shows a QNMR chromatogram of crocin obtained as described inExample 2.

DETAILED DESCRIPTION OF INVENTION

While various embodiments of the present invention about compositionsare discussed below, it should be appreciated that the present inventionprovides some of many applicable inventive concepts that can be embodiedin a wide variety of specific contexts. The specific embodimentsdiscussed herein are merely illustrative of a few specific ways to makeand use the invention and do not delimit the scope of the invention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

This invention reveals nutraceutical/therapeuticcompositions/formulations and/or regimens comprising unique combinationswith meaningful, quantitative, and sufficient amount of enriched orpurified or high purity natural crocin and/or crocetin and possibleother health beneficial phytochemicals and/or extracts and/or vitaminsand/or health beneficial minerals.

This invention to provide a safe and natural nutraceutical/therapeuticcomposition for preventing, decreasing and treating cancers, age-relatedneurodegenerating disease (Alzheimer's and Parkinson's diseases), brain,heart, liver, kidney diseases, eye and circulations diseases, diabetes,inflammations, skin damages, signs of aging of the skin and otherconditions. This invention provides a safe and naturalnutraceutical/therapeutic composition for enhancing/restoring functionof brain, heart, liver, eye, kidney, pancreas, skin and protecting themfrom oxygen radical stress, toxins, metals, alcohol/ethanol inducedinjury/damage/impairment. This invention provides a safe and naturalnutraceutical/therapeutic composition for enhancing/restoring inlearning and memory. This invention prevents/improves/treats abovementioned diseases and conditions by the use of a specific compositionor compositions of crocin and/or crocetin or combination of crocin andcrocetin and possible selection of other effective or health promotingphytochemicals, amino acids, vitamins or minerals. The invention is alsouseful but not limited to above mentioned diseases, disorders andsub-health conditions. These compositions can be considered as atherapy. These compositions can also be considered as improvements inhuman nutrition in that they present new combinations of phytochemicals,or amino acids, or vitamins useful in reducing above mentioned diseaserisks.

Crocin and other crocetin glycosides are major color components andphytochemicals of the stigmas of saffron (Crocus sativus L.) and thefruits of gardenia (Gardenia jasminoides Ellis). Both saffron andgardenia fruits have been traditionally used and listed as foodadditives. Crocin, crocetin and crocetin natural glycosides from saffronor gardenia fruits are considered safe as extensive studies found crocinhave no toxic effect on normal cells and protect normal cells. Due tolimitation of saffron source and its expensiveness, it is cost forbiddento commercially enrich or purify crocin and/or crocetin from saffron.Saffron quality variation and a high amount of adulterant on the saffronmarket also hinder its use in quality products. Enriching andpurification of crocin and crocetin from commercial gardenia yellow,gardenia extract or directly from gardenia fruits provides affordableand high purity crocin and/or crocetin for quantitative and amountconsistent applications in this invention. The enriched and purifiedcrocin and/or crocetin of this invention to be used in supplements ortherapeutic products are safe and effective for enhance health, protect,prevent and lower risk of above mentioned diseases and conditions. Useof enriched or purified natural crocin and/or crocetin in therapeuticcompositions or formulations is essential in this invention.Particularly an injectable requires high purity and high quality crocinand/or crocetin.

The crocin and/or crocetin used in this invention is the enriched orpurified form with crocin and/or crocetin content of at least 50%,preferably at least 80%, more preferably at least 90%, in particularcases at least 99%, manufactured under conditions to meet food orpharmaceutical standards. Said the crocin can include Crocin-I(Crocetin-di-β-D-gentiobiosyl ester), Crocin-II(Crocetin-β-D-gentiobiosyl-β-D-glucosyl ester), Crocin-III(Crocetin-mono-β-D-gentiobiosyl ester), Crocin-IV (β-D-monoglucosideester of monomethyl α-crocetin), Crocetin-di-(β-D-glucosyl) ester,Crocetin-mono-β-D-glucosyl ester, 13-cis-crocetin di(β-D-gentiobiosyl)ester and 13-cis-crocetin β-D-gentiobiosyl-β-d-glucosyl ester, etc.naturally existed crocetin derivatives in saffron or Gardenia fruits.

This invention has a number of advantages over the use of saffron andsaffron extracts. Because crocin and/or crocetin can be enriched andpurified from an abundant and safe source, gardenia yellow, gardeniafruit or gardenia extract through a simple and effective method, themanufactured crocin and/or crocetin are highly enriched and purified incomparison to saffron. Processes described herein, without using toxicsolvent or generating large amount of waste, are environmentallyfriendly. Enriched and purified crocin and/or crocetin with purity atleast 50% up to 99% have significant reduced or no undesirablecomponents provide safer products. Unlike saffron which varies in crocincontent, Crocin and/or crocetin described in compositions herein providequantitative, quality consistent and effective dosage for preventing andtreating cancers, neurodegenerative disorders such as Alzheimer's andParkinson's diseases, age-related macular degeneration, and otherdiseases or conditions. High purity crocin and/or crocetin describedherein are particularly useful in compositions for injection orinfusion.

Crocin and/or crocetin are typically analyzed and detected by HPLC atwavelength of 440 nm. However, if a component or components in a saffronor gardenia extract possess no crocetin or carotenoid-like corestructure, such components will not be detected at 440 nm. Hence, todetermine crocin purity in saffron or gardenia extracts, it is essentialto analyze the sample or samples with crocin standard at differentconcentrations to establish a linear line under the same conditions on aHPLC instrument. Preferably, crocin purity determination can also bedone by Quantitative Nuclear magnetic resonance (NMR) spectroscopy.

An exemplary embodiment method of the invention includes but is notlimited, for example:

a. Purification of Crocin and/or Crocetin:

20 g of Commercial gardenia yellow D500 was weighed into a centrifugebottle, add 3 times of 80% ethanol in volume of gardenia yellow weight,cover the bottle and stir at 35° C. for 15 to 20 minutes in dark,separate soluble in supernatant after centrifugation at 10,000×g for 10minutes, supernatant was collected in flask, repeat 5 times of theaddition of ethanol dissolution and separation of soluble supernatant,the collected and combined supernatants was sealed and put into −10° C.freezer in dark for 15 to 20 days, then filter to separate crystals fromsolution and washed with acetone, 5.7 g crocin was obtained, dissolvethis crocin in 360 ml 80% ethanol and recrystallize at −10° C. givepurer crocin, wash with acetone, dry to obtain about 4 g; high puritycrocin is further obtained by column chromatography through common stepsincluding dissolving the product in 30% ethanol, passing the solutionthrough a column filled with macroporous resin A-5 to adsorb crocin withresin, washing with distilled water and 30% ethanol to removeimpurities, eluting the column with 95% ethanol to desorb pure crocinfrom the resin, collecting the eluted crocin solution, concentrating anddrying. A flow chart of crocin and/or crocetin purification is shown inFIG. 1.

Analysis of Crocin by HPLC:

Preparation of linear solution: Accurately weighed 11.9 mg Crocin Istandard in 10 ml volumetric flask, add methanol and water (1:1) todissolve crocin and make to the scale as mother solution. Aliquot theprepared mother solution to make a series of diluted standard solutions.Standard solutions were subjected to HPLC analysis to prepare standardcurve. 5 μml of the prepared solution was injected into HPLC instrument.HPLC instrument is an Agilent 1260/6120 and equipped with Agela VenusilXBP C18 column (4.6×150 mm, 5 μm) and column temperature at 40° C. Otherconditions and elution gradient were listed below:

Mobile Phase: A: 4 L H2O 2O (with 1.5 ml TFA)

-   -   B: 4 L Acetonitrile (with 0.75 ml TFA)

Gradient

Time (min) B %  0.01 0 10.00 60 15.00 100 20.00 100 Post run: 4.5 min

Flow rate: 1 ml/min

Wave length: 440 nm

Column Temp: 40° C.

Corresponding HPLC peak areas and concentrations of crocin samples werelisted in table 1:

TABLE 1 Crocin Standards Peak area Conc (μg/ml) Std. 1 3119.7 119 Std. 22004.7 79.33 Std. 3 1507.4 59.5 Std. 4 735.6 29.75 Std. 5 168.8 7.44

A linear equation of y=26.361×−48.186 (R²=0.9994) was obtained bycalculation. Sample with crocin concentration in the range of 7.44 μg/mland 119 μg/ml conforms to the linear relation.

b. Analysis of Crystallization Sample:

Accurately weigh 18.8 mg crystallization sample in 10 ml volumetricflask, add methanol and water (1:1) to dissolve sample and make to thescale resulting in 188 μg/ml (18.8 mg/10 ml) concentration, andaccurately transfer 5 ml into another 10 ml volumetric flask, addmethanol and water (1:1) to scale and make 94 μg/ml sampleconcentration; 5 μl of the prepared sample solution was injected to HPLCunder same conditions described in making standard linear equation (seeFIG. 1); Calculate sample purity by using the formula of:

Crocin Purity(100%)=Concentration of the solution undertest/Concentration of crocin samples*100

Measured and calculated results by HPLC method are shown in table 2.

TABLE 2 Sample Area C1 (μg/ml) W (mg) C2 (μg/ml) Purity % 1 3846.7147.75 18.8 188 78.59 2 1886 73.37 9.4 94 78.06c. Analysis of Crocin by QNMR:

Accurately weigh 5-10 mg of crystallization sample and maleic acid intoNMR tube, add 0.6-1.0 ml of DMSO-d6 (>99% atom-% D) into the tube andshake to dissolve both sample and maleic acid. It is subjected toquantitative H-NMR analysis. NMR instrument is Varian 400MR. Test formeasurement is set at Pulprog=zg45, d1=15, d2=19, and nt=16. δ 1.97(12H) is selected as quantification peak; δ 6.25 is internal standardquantification peak (see FIG. 2). After measurement, results arecalculated by the formula:

Assay of sample=[I(a)×MW(a)×N(b)×W(b)×A(b)]/[I(b)×MW(b)×N(a)×W(b)]

I(a): Area of sample selected peakI(b): Area of internal standard peakMW(a): Sample molecular weightMW(b): Internal standard molecular weightW(a): Sample weightW(b): Internal standard weightN(a): Number of proton of selected sample peakN(b): Number of proton of selected internal standard peakA(b): Purity of internal standardMeasured and calculated results by QNMR method are shown in table 3.

TABLE 3 Ratio of area of Sample Wt. Standard Wt. selected peak to Purityof Test No. (mg) (mg) standard's Sample 1 9.7 6.2 0.795:1 77.30% 2 9.46.9 0.871:1 81.10% Average 79.20%

The nutraceutical/pharmaceutical compositions with enriched or purifiedcrocin and/or crocetin of the invention can be formed alone or incombination with one or more of health promoting phytochemicals or foodextracts containing effective amount of phytochemicals including:acteoside, aloenin, aloesin, aloin, alpinetin, atractylenolide,atractylodin, aurantio-obtusin, cimigenol, cimifugin, cimiside,garcinone, ascorbic acid, astragalin, quercetin, resveratrol,pterostilbene, curcumin, demethoxycurcumin, bis-demethoxycurcumin,theaflavin, theaflavin-3,3′-digallate, theaflavin-3-gallate,theaflavin-3′-gallate, L-theanine, anthocyanidins, anthocyanins,catechin, epicatechin, gallocatechin, epigallocatechin, epicatechingallate, gallocatechin gallate, epigallocatechin gallate, procyanidin,chlorogenic acid, cardamonin, arctigenin, arctiin, asiatic acid,asiaticoside, bergamotin, bergapten, betaine, dioscin, galangin,cimicifugoside, cinnamic acid, ferrulic acid, fumaric acid, α-lipoicacid, carnosine, L-carnitine, caffeic acid, ellagic acid, maslinic acid,phenylethyl caffeate, caffeic acid phenethyl ester, theobromine,theophylline, caffeoylquinic acid, ursolic acid, allicin, gingerol,shogaol, ginkgolide, ginkgetin, ginsenoside, astragaloside,cycloastragenol, danshensu, danshenol, danshenxinkun, tanshinone,tanshindiol, rosmarinic acid, dosmin, nobiletin, tangeretin, luteolin,lutein, β-lycopene, zeaxanthin, tyrosol, hyperin, hyperoside, quercetin,quercetrin, isoquercitrin, hydroxytyrosol, rosarin, β-rosasterol,rosavin, rosin, punicalagin, punicalin, myricetin, myricitrin,kaempferol, dihydromyricetin, apigenin, naringin, naringenin, honokiol,magnolol, mangiferin, mangostin, hesperetin, hesperidin, lupeol,indole-3-carbinol, genistein, genistin, daidzein, daidzin, cynarin,bilobalide, bilobetin, epimedin, sulforaphane, phloretin,phloretin-xyloglucoside, phloridzin, proanthocyanidins, procyanidin B1,procyanidin B2, procyanidin C1, silibinin, rutin, wogonin, morin,morusin, mulberroside A, mulberroside B, glycyrrhizic acid,glycyrrhetinic acid, linarin, protodioscin, protogracillin, synephrine,rebaudioside A, stevioside, vitexin, isovitexin, vitexin-4,vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, vitexin-4′-rhamnoside,alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol,etc.

A food extract that should contain effective amount of phytochemicalscan come from one but not limited to the following sources: bilberry,blueberry, cranberry, raspberry, cherry, mulberry, pomegranate, purplecorn, strawberry, grapes, black berry, gooseberry, black currants,grape, cocoa beans, coffee beans, pine bark, cardamom, cinnamon bark,ginseng, astrgalus, rodiola, garcinia, ginger, ginkgo, citrus fruit,grape skins, grape seeds, hawthorn, artichoke, broccoli, broccoli seeds,apple, olive, orange, lemon, pepper, soybean, mango, tea leaves, tomato,turmeric, cabbage, purple corn, black rice, bitter lemon, stevia, lohan, goji (wolfberry), sea buckthorn, kudzu, clove, hemp, cassia,magnolia, nutmeg, jujube, honeysuckle, poria, bellflower, lotus, basil,sesame, angelica, cimicifuga, epimedium, schisandra, salvia, licorice,ligustrum, ophiopogonis, aloe, dodder, fenugreek, gotu kola, purslane,tribulus, etc. The above components of the compositions of the inventionshould have, individually, effective levels of purity to meet theobjectives of the invention. The components can be standardized fordosage level based on purity and amount used.

The nutraceutical/pharmaceutical compositions can further include one ormore free amino acids or peptides, such as arginine, lysine, methionine,histedin, leucine, isoluceine, alanine, phenyalanine, asparingine,aspartic acid, tryptophane, proline, threonine, cysteine,selenocysteine, serine, taurine, tyrosine, valine, glycine, glutamine,glutamic acid, ornithine, carnosine, L-carnitine, glutathione.

The nutraceutical/pharmaceutical compositions can further include one ormore vitamins or minerals, including, but not limited to, vitamin A,vitamin C, vitamin B 1, vitamin B2, vitamin 33, vitamin B6, vitamin B12,vitamin D, vitamin E, vitamin K (and derivatives), calcium, sodium,potassium, chromium, vanadium, magnesium, manganese, selenium, copper,molybdenum, boron, vanadium, and/or iron (and derivatives) (preferablyin amounts less than the RDA).

The nutraceutical/pharmaceutical composition of the invention may beadministered in any route that is appropriate, including but not limitedto oral, parenteral (Intravenous, intramuscular, intraperitoneal,intrasternal, subcutaneous, intraarticular injection and infusion),percutaneous, rectal, mucosal, intranasal or topical (transdermal, as bypowders, ointments, creams, sprays, drops or patches) administration.Ophthalmic formulation, ear drops, solutions, and eye ointments are alsocontemplated as being within the scope of this invention. The mostsuitable route may depend upon the condition and disorder of therecipient.

In certain embodiments more than one dose comprising an effective amountof crocin and crocetin is administered to the human (e.g., two or moredoses spaced over time, each dose comprising an effective amount ofcrocin and crocetin). The effective amount of crocin and crocetin can bein compositions in combination with one or more active components ofphytochemicals and or amino acids or peptides previously mentioned.

In some embodiments compositions comprise with one or more carbohydratenutrients. For example, the carbohydrate nutrient may be selected fromthe group consisting of: rice oligodextrin, amylase, amylopectin,glucose, sucrose, fructose; maltodextrin, maltose, isomaltulose,leucrose, trehalulose, ribose, trehalose.

The applications and dosage forms of nutraceutical/pharmaceuticalcompositions for oral administration can be liquids, beverages, tablets,soft gels, capsules, pills, caplets, gums, dragees, granules, powders,or effervescent tablets, sprays, functional foods.

A solid nutraceutical/pharmaceutical composition for oral administrationmay optionally contain, in addition to the above enumeratednutraceutical/pharmaceutical composition ingredients or compounds:carrier materials such as corn starch, acacia, gelatin, malt,tragacanth, microcrystalline cellulose, kaolin, dicalcium phosphate,calcium carbonate, sodium chloride, alginic acid, lactose, glucose,sucrose, and the like; disintegrators including, microcrystallinecellulose, alginic acid, and the like; binders including acacia,methylcellulose, ethyl cellulose, sodium carboxymethylcellulose,polyvinylpyrrolidone, hydroxypropyl methylcellulose, and the like; andlubricants such as magnesium stearates, stearic acid, silicone fluid,talc, oils, waxes, colloidal silica, and the like. In addition to activeingredients, an effervescent tablet composition may contain mixtures ofacids (like citric, tartaric, malic and fumaric acid or combinationthereof) and carbonates like sodium, potassium bicarbonate or carbonatethat release carbon dioxide when dissolved in water and water solublebinder (starches, natural gums, cellulose gums, microcrystallinecellulose, methylcellulose, cellulose ethers, ethylcellulose, sodiumcarboxymethylcellulose, gelatin, dextrose, lactose, sucrose, sorbitol,mannitol, polyethylene glycol, polyvinylpyrrolidone, pectins, alginates,polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols and mixturesthereof) and lubricant (sodium benzoate, polyethylene glycol, L-leucine,adipic acid, and combinations thereof). A composition can also includeother ingredients including, e.g., flavor agents, fillers, surfactants,color agents, and sweeteners. The usefulness of such excipients is wellknown in the art. A composition optionally comprises one or moreadditional coatings surrounding the core and/or the control releasingcoat such as moisture barrier coats, enteric coats or coatings thataffect the physical integrity and/or appearance of the nutraceuticalcomposition.

In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usinglactose or milk sugar as well as high molecular weight polyethyleneglycols and the like.

A liquid nutraceutical composition for oral administration in connectionwith a method can be prepared in water or other aqueous vehicles. Inaddition to the above enumerated nutraceutical/pharmaceuticalcomposition ingredients or compounds, a liquidnutraceutical/pharmaceutical composition can include suspending agentssuch as, for example, alginates, pectin, kelgin, carrageenan, acacia,methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and the like.The liquid nutraceutical/pharmaceutical compositions can be in the formof a solution, emulsion, syrup, gel, powder or elixir including orcontaining wetting agents, sweeteners, and coloring and flavoringagents. Various liquid and powder nutraceutical compositions can beprepared by conventional methods.

The nutraceutical/pharmaceutical compositions for parenteral andpercutaneous administration comprise pharmaceutically acceptable sterileaqueous or nonaqueous solutions, dispersions, suspensions or emulsionsand sterile powders for reconstitution into sterile injectable solutionsor dispersions. Intravenous administration is likely one of the bestroutes in delivery of crocin and crocetin for most effective preventionand treatment of cancers and other diseases and conditions. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (propylene glycol, polyethylene glycol,glycerol, and the like), suitable mixtures thereof, vegetable oils (suchas olive oil) and injectable organic esters such as ethyl oleate.Further, the injections may contain stabilizers, solubilizers,suspending agents, emulsifiers, soothing agents, buffers, preservatives,isotonic agents, antibacterial and antifungal agents, etc. Theinjectable compositions are sterilized in the final formulation step orprepared by sterile procedure. The nutraceutical/pharmaceuticalcomposition of the invention may also be formulated into a sterile solidpreparation, for example, by freeze-drying, and the sterile solidpreparation can be dissolved in a solvent, sterile injectable water,injectable saline or other sterile diluent(s), to form an injectablesolution for immediate injection.

A pharmaceutical composition solution for parenteral administration maygenerally be prepared by dissolving the compound in a medium, subjectingthe resulting solution to filtration for sterilization, filling thesolution in vials or ampoules or glass bottles or suitable plastic bags,and sealing the vials or ampoules or bottles or bags. It is alsopossible to freeze-dry the composition and fill the resulted powder invials, and then eliminate the moisture in vacuum to improve stability.Parenteral suspensions can be prepared by substantially the same methodas that applied to solutions for parenteral administration; however, thesuspensions can preferably be manufactured by suspending the activeingredient in a medium, and then subjecting the result to sterilizationby using ethylene oxide or the like. Furthermore, surface active agents,moistening agents and so forth may also be added so that a uniformdispersion of the active ingredient can be obtained.

Compositions for rectal administration are preferably suppositorieswhich can be prepared by mixing the active components of this inventionwith suitable non-irritating carriers such as cocoa butter, polyethyleneglycol or a suppository wax which are solid at ambient temperature butliquid at body temperature and therefore melt in the rectum and releasethe active compound.

Compositions for topical or transdermal administration of this inventioncan be prepared as ointments, pastes, creams, lotions, gels, powders,solutions, sprays, inhalants or patches. The active component is admixedunder sterile conditions with a pharmaceutically acceptable carrier andany needed preservatives or buffers as may be required. The ointments,pastes, creams and gels may contain, in addition to an active compoundof this invention, animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc and zinc oxide, or mixturesthereof. Powders and sprays can contain, in addition to the compounds ofthis invention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compositions of this invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to theactive components of this invention, stabilizers, preservatives, and thelike. The preferred lipids are the natural and synthetic phospholipidsand phosphatidylcholines (lecithins) used separately or together.Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

In certain embodiments the amount of crocin or crocetin or thecombination of both is from about 1.0 mg to about 7000 mg per dose, fromabout 50 mg to about 500 mg per dose for prevention and protection, orfrom about 200 mg to about 2000 mg per dose, or from about 200 mg to 500mg per dose. In certain embodiments the effective amount of crocin andcrocetin is from about 0.25 mg/kg bodyweight of the human to about 50mg/kg bodyweight of the human per dose. The dose, and perhaps the dosefrequency, can vary according to the age, body weight and conditions ofindividual patient. The purity of the ingredients and the presence ofadded diluents, emulsifiers and other additives must be taken intoconsideration in determining the dosage.

In a preferred form the invention provides a dietary supplementcomposition wherein supplement capsules are prepared by simply use ofdry or solid compositions as filler in soft and hard-filled gelatin orvegetable capsules for oral administration. Prepared capsules are orallyadministered as part of a prepared food. One example formula includesthe following active ingredient presented in parts in weight: about 200parts crocin and crocetin, about 150 parts green tea extract, about 50parts curcumin, about 50 parts resveratrol, about 25 parts Panax ginsengextract, about 15 parts α-lipoic acid, and about 10 parts L-carnitine. Acomposition containing this formula and carriers may be conventionallypresented in unit dosage form and prepared by methods, fill in ascapsules or press into tablets, well known in the art of supplement. Thetotal daily dose (in single or divided doses) ranges from about 100 mgper day to about 2000 mg per day, or about 200 mg per day to about 4000mg per day. In some embodiments, the total daily dose may range fromabout 50 mg to about 5000 mg per day. A powder mixture of this formulacan also be used to prepare functional foods. More examples providedlater.

In another preferred form the invention provides a therapeuticcomposition wherein soluble effervescent tablets are prepared bycompression. Compare to conventional tablet and capsules, effervescenttablets have major advantage that the drug product is already insolution at the time it is consumed. The absorption is faster and activeingredients are delivered to the stomach at a pH that is just right forabsorption. Because effervescent tablets dissolve fully in a bufferedsolution, it prevents gastric acids from interacting with the activeingredients and reduces causes of stomach and esophageal upsets.Effervescent tablets also enhance the absorption of a number of activeingredients, compared to conventional formulations. This is because thecarbon dioxide created by the effervescent reaction can induce enhancedactive-ingredient permeability due to an alteration of the paracellularpathway. The paracellular pathway is the primary route of absorption forhydrophilic active ingredients in which the solutes diffuse into theintercellular space between epithelial cells. It is postulated that thecarbon dioxide widens the intercellular space between cells, which leadsto greater absorption of active ingredients. One exampled formulaincludes: 1500 mg citric acid, 800 mg potassium bicarbonate, 800 mgsodium bicarbonate, 160 mg sodium carbonate, 250 mg crocin and crocetin,60 mg polyethylene glycol 6000, 50 mg aspartame, 30 mg flavorant. Thematerial of this formula can be blended and pressed into appropriatesize of soluble effervescent tablets. For effective protection andprevention, a dosage unit of this formulation will preferably be from0.5 g to 10 g. The doses and these individual ingredients can be variedby up to 50% of the above values, preferably varying by no more than25%. For therapeutic propose and treatment, a dosage or multi-dosages of1 g to 20 g per day is sufficient and effective for patients.

In yet another preferred form, a sterile injectable solutions can beprepared by incorporating crocin and crocetin prepared underpharmaceutical procedure in the required amount in an appropriatesolvent with one or a combination of ingredients enumerated above, asrequired, followed by filtered sterilization. Generally, dispersions areprepared by incorporating the active compound into a sterile vehiclewhich contains a basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, the preferredmethods of preparation are vacuum drying and freeze-drying which yieldsa powder of crocin and crocetin plus any additional desired ingredientfrom a previously sterile-filtered solution thereof. One exampleformulation includes preparation of a solution with crocin and/orcrocetin, which is purified under pharmaceutical grade conditions, andcyclodextrin, or mannitol, or sorbitol or maltitol, fill in glass vialswith designated volume/dosage and freeze-dry to get powder form andaseptically seal the vials. An injectable solution is re-constitutedwith sterile injectable water or saline or 5% dextrin before injection.Dosage of purified crocin and/or crocetin ranges from 10 mg to 5000 mgper day, preferably 50 mg to 1000 mg per day, more preferably 100 mg to500 mg per days.

A topical formulation of this invention, one exampled compositioncontains a combination of crocin, crocetin, and one or more α-lipoicacid, a carnosine, and a carnitine, is particularly advantageous becauseof the multi-pronged effect these ingredients have for addressing theaging process. Each of α-lipoic acid, L-carnitine, and carnosine areproduced by the body and their secretion generally decrease with age,and the topical application of these or related compounds providesprotection against loss due to age. These ingredients are alsoantioxidants.

The topical formulation will preferably comprise crocin and/or crocetinthereof in an amount of from about 0.01 to 50% by weight, based on thetotal weight of the composition, or more preferably in an amount of fromabout 0.1 to 7.0% by weight, based on the total weight of thecomposition. The formulation will preferably comprise L-carnitinethereof in an amount of from about 0.01 to 50% by weight, based on thetotal weight of the composition, or more preferably in an amount of fromabout 0.5 to 2.0% by weight, based on the total weight of thecomposition. The formulation will preferably comprise carnosine thereofin an amount of from about 0.01 to 50% by weight, based on the totalweight of the composition, or more preferably in an amount of from about0.1 to 5.0% by weight, based on the total weight of the composition.

Following examples are presented to further explain and illustrate theinvention and are not to be taken as limiting in any regard. Unlessotherwise indicated, all parts and percentages are by weight.

COMPOSITION EXAMPLES Example 1

This example provides a preferred, but not limited, dosage form of acomposition of the invention. Gelatin or vegan capsules are produced bypreparing a mixture of the following ingredients with filler by grindingunder a vacuum to assure intimate mixing and a dry character, and thenfilling individual gelatin capsules with a total of 1000 mg ascomprising of following:

200 mg  crocin and/or crocetin 150 mg  green tea extract 50 mg curcumin50 mg resveratrol 25 mg Panax ginseng extract 15 mg α-lipoic acid, and10 mg L-carnitine

These capsules are consumed in a regimen effective to prevent or treatcancers and other conditions and diseases, preferably taking once in themorning and once in the evening.

Example 2

This example provides another preferred, but not limited, composition ofthis invention. Tablets are produced by preparing a mixture of thefollowing ingredients with excipient through steps by blending, drygranulating, milling, blending, compressing, and coating. A compositioncomprises enriched and purified crocin and/or crocetin and otherphytochemicals or extracts as following:

200 mg crocin and/or crocetin 200 mg green tea extract 100 mg curcumin100 mg Grape seed extract  50 mg Panax ginseng extract  50 mg Rhodiolarosea extract  50 mg Ginkgo biloba extract

A daily supplement dosage of 100 mg to 1000 mg is useful in preventingand delaying cancers and neurodegenerative diseases, enhancing brain andmental health, improving cognitive, learning and memory ability,protecting liver, heart, lung, kidney, eye, skin, nerves, normal cells.

Example 3

This example provides a preferred, but not limited, dosage form of acomposition of the invention. Gelatin or vegan capsules are produced bypreparing a mixture of the following ingredients with filler by grindingunder a vacuum to assure intimate mixing and a dry character, and thenfilling individual gelatin capsules with a total of 1000 mg ascomprising of following:

200 mg crocin and/or crocetin 500 mg dihydromyricetin  50 mg resveratrol 50 mg artichoke leaf extract

These capsules are consumed in a regimen effective to protect liver frominjury and alcohol damage, or treat liver cancer and/or restore liverfunction, prevent and/or treat other conditions and diseases, preferablytaking once in the morning and once in the evening, or preferably takingprior to consume alcohol.

Example 4

This example provides a preferred, but not limited, dosage form of acomposition of the invention. Gelatin or vegan capsules are produced bypreparing a mixture of the following ingredients with filler by grindingunder a vacuum to assure intimate mixing and a dry character, and thenfilling individual gelatin capsules with a total of 1000 mg ascomprising of following:

250 mg crocin and/or crocetin 200 mg citrus extract (90%polymethoxylated flavones, nobiletin & tangeretin) 100 mg curcumin  50mg resveratrol

These capsules are consumed in a regimen effective for prevention andtreatment of cancer and lowering risk of cancers and other diseases orconditions, preferably taking once in the morning and once in theevening in the middle of meal.

Example 5

This example provides a preferred, but not limited, composition of thisinvention for eye health. Tablets are prepared by preparing a mixture ofthe following ingredients with excipient through steps by blending, drygranulating, milling, blending, compressing, and coating. A compositioncomprises enriched and purified crocin and/or crocetin and otherphytochemicals or extracts as following:

200 mg crocin and/or crocetin 200 mg lycopene 100 mg beta-carotene 100mg bilberry extract  50 mg lutein  25 mg zeaxanthin

These tablets are consumed in a regimen effective to prevent and treatof age-related macular degeneration (AMD), increase blood circulation inretina, protect retina and brain from toxin- or light-induced stress,improve and maintain eye sight and brain function, and lower risk ofcancers and other diseases or conditions, preferably taking once in themorning and once in the evening in the middle of meal.

Example 6

This example provides a preferred, but not limited, therapeuticallyinjectable/infusion composition of this invention. A sterileinjectable/infusion composition is prepared in amber vials or bottles inlyophilized powder form by steps: quantitatively mixing 5 g high puritycrocin and/or crocetin (at least a purity of 98%, preferably at least99%) with 20 g or 40 g pharmaceutical grade mannitol, dissolving themixture in a suitable solvent 400 ml or 800 ml distilled or injectablewater, sterilizing by filtering the solution through 0.15-0.22 μmsterilized filtration membrane, distributing into sterilized amber vialsor bottles, freeze-drying, sealing vials or bottles, and labeling andpacking to obtain the products. To inject or infuse the product to asubject, a solution of the product is reconstituted by adding, shakingand dissolving in suitable amount of injectable water or physiological(0.7% w/w) saline solution.

A. A Reconstituted Injection Lyophilized Vial Contains:

 50 mg crocin and/or crocetin 200 mg mannitol  5 ml physiological (0.7%w/w) saline solution

B. A Reconstituted Infusion Lyophilized Bottle Contains:

 250 mg crocin and/or crocetin 2000 mg mannitol  50 ml physiological(0.7% w/w) saline solution

This injectable or infusion form of this invention is useful in treatingvarious cancers, neurodegenerative disorders such as Alzheimer's andParkinson's diseases, other diseases and conditions.

Example 7

This example provides a preferred, but not limited, dosage form of acomposition of this invention. Effervescent tablets are prepared byfollowing steps: a. mix anhydrous citric acid with crocin and/orcrocetin. b. make granulates by adding 65% citric acid solution underagitation and subsequently drying at low temperature to relativehumidity of the granule to less than 0.15%. c. mix granules at lowhumidity with anhydrous sodium bicarbonate, flavorant, aspartame, andpolyethylene glycol (PEG) 6000. d. press to form the effervescenttablets and magnesium stearate is used as an external lubricant to avoidsticking during the tableting operation. Average size of the tablets is3.85 g with diameter of 23 mm and thickness of 3.15 to 3.25 mm. e. pack10 tablets in a re-sealable HDPE container. An exemplary effervescentcomposition comprises the following:

200 mg crocin and/or crocetin 250 mg dihydromyricetin 5700 mg  anhydrouscitric acid 12000 mg  sodium bicarbonate 300 mg PEG 6000 200 mgflavorant (lemon flavor) 200 mg aspartame

A daily consumption of one tablet by dissolving the tablet in 6 oz. ofwater at room temperature and drinking is useful and effective forprotecting liver from alcohol or over dose iron or other heavy metalcaused damages, protecting lung from injury or cancers caused by smokeor smog, enhancing heart functions, preventing or treating cancers orother diseases or conditions.

Example 8

This example provides a preferred, but not limited, dosage form of acomposition of this invention for application in food or drink. Powderof crocin and/or crocetin with rebaudioside A, glycyrrhizic acidammonium salt, and erythritol in a ratio of 25:50:50:2875 by weight ismixed. The pre-mixed powder product can be directly used as powder formpacked in sachets or packets or a moisture and light shield containerwith a size pre-determined scoop. The pre-mixed powder can also befurther formulated and processed as cubes, granules for use in sachetsor packets, and tablets. 2.5 grams of the pre-mixed powder is added to aserving of non-fat and non-sugar yogurt (6 oz.) and followed withstirring to homogenous. A nice yellow colored and sweetened yogurt with25 mg crocin and/or crocetin but no extra calories is served. Inapplication to a drink, 2.5 grams of the pre-mixed powder or formedcubes, granules or tablets, which are readily soluble, is added to aserving (8 oz.) of water, or drink or juice. Flavoring can be added atuser's choice or preference. Stir with a spoon for 1 to 5 minutes. Adrink with 25 mg crocin and/or crocetin but no extra calories is served.A composition list is provided as comprising of following:

100 mg crocin and/or crocetin 200 mg rebaudioside A 200 mg glycyrrhizicacid ammonium salt 9500 mg  erythritol

This composition in products is consumed daily in a regimen effectivefor eye health and brain health, to prevent or delay age-related maculardegeneration, to prevent or treat mild-to-moderate Alzheimer's disease,to prevent and reduce risks of cancers and heart diseases, and toenhance overall health.

The above description is intended to enable the person skilled in theart to practice the invention. It is not intended to detail all of thepossible modifications and variations which will become apparent to theskilled worker upon reading the description. It is intended, however,that all such modifications and variations be included within the scopeof the invention which is seen in the above description and otherwisedefined by the following claims. The claims are meant to cover theindicated elements and steps in any arrangement or sequence which iseffective to meet the objectives intended for the invention, unless thecontext specifically indicates the contrary.

Patent Citations:

Publication Cited Patent Filing date date Applicant Title CN102516325 ANov. 15, Jun. 27, 2012 Method for 2011 producing crocin with higher than95% purity from gardenia WO2004078695 Mar. 3, Sep. 16, 2004 KoichiHarada, Method for the A1 2004 Riken Vitamin Co, purification ofMasahiro crocetin Takahashi WO2010094745 Feb. 18, Aug. 26, 2010 OmnicaGmbh Hydrolysate of A1 2010 crocin US20100210572 Feb. 17, Aug. 19, 2010Thomas Hydrolysate of A1 2010 Eidenberger crocin WO2004056201 Dec. 19,Jul. 8, 2004 Shri Gopal Method for the A1 2002 Agarwal, Vijaipreparation of Kant Agnihotri, saffron pigment Council Scient Ind andflavor Res, Ghulam Nabi concentrate Qazi, Om Prakash Suri, RajinderKumar Thappa U.S. Pat. No. 7,351,844 B2 Feb. 25, Apr. 1, 2008 DiffusionBipolar trans 2003 Pharmaceuticals carotenoid salts Llc and their usesUS20130156746 Aug. 25, Jun. 20, 2013 Persavita Ltd. Composition and A12011 method of manufacture US20110236481 Jun. 9, Sep. 29, 2011 CedricBourges Use of saffron A1 2011 and/or safranal and/or crocin and/orpicrocrocin and/or derivatives thereof as a satiety agent for treatmentof obesity

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1. A nutraceutical or therapeutic composition comprising at least one ofcrocin and crocetin, wherein crocin and/or crocetin is extracted,enriched and/or purified from natural source.
 2. The nutraceutical ortherapeutic composition according to claim 1, comprising both crocin andcrocetin, wherein both crocin and crocetin are extracted, enrichedand/or purified from natural source.
 3. The nutraceutical or therapeuticcomposition according to claim 1, wherein crocin and/or crocetin isextracted, and enriched and/or purified from natural source according tothe following steps: (a) dissolving gardenia fruit extract or gardeniayellow in 40-99% ethanol at temperature range from 10° C. to 70° C.; (b)filtration, crystallization and re-crystallization at temperature rangefrom −20° C. to 4° C., followed by filtration, if necessary; (c)purification/separation by column chromatography, elution, concentrationand drying to obtain enriched and/or purified natural crocin and/orcrocetin.
 4. The nutraceutical or therapeutic composition according toclaim 1, wherein crocin and/or crocetin is extracted, and enrichedand/or purified from natural source according to the following steps:(a) dissolving gardenia fruit extract or gardenia yellow in 60-90%ethanol at temperature range from 30° C. to 60° C.; (b) filtration,crystallization and re-crystallization at temperature range from −10° C.to 0° C., followed by filtration, if necessary; (c)purification/separation by column chromatography, elution, concentrationand drying to obtain enriched and/or purified natural crocin and/orcrocetin.
 5. The nutraceutical or therapeutic composition according toclaim 1, wherein the natural source is from at least one of thefollowing: Crocus sativus L (Saffron), Crocus boryi ssp. tournefortii,Crocus boryi ssp. boryi and Crocus niveus, fruits of gardenia includingGardenia jasminoides Ellis, G. jasminoides Ellis. var. fortuniana(Lindl) hara. and G. jasminoides f longicarpa.
 6. The nutraceutical ortherapeutic composition according to claim 1, wherein the enriched orpurified natural crocin is at least one of the following: crocin-I(crocetin-di-β-D-gentiobiosyl ester), crocin-II(crocetin-β-D-gentiobiosyl-β-D-glucosyl ester), crocin-III(crocetin-mono-β-D-gentiobiosyl ester), crocin-IV (β-D-monoglucosideester of monomethyl α-crocetin), crocetin-di-(β-D-glucosyl) ester,crocetin-mono-β-D-glucosyl ester, 13-cis-crocetin di(β-D-gentiobiosyl)ester, 13-cis-crocetin β-D-gentiobiosyl-β-d-glucosyl ester, and the likethat naturally existing in saffron or gardenia fruits or gardeniayellow.
 7. The nutraceutical or therapeutic composition according toclaim 1, wherein the enriched or purified crocetin is from saffron orgardenia fruits or gardenia yellow.
 8. The nutraceutical or therapeuticcomposition according to claim 1, wherein crocin and/or crocetin isextracted, enriched and/or purified from natural source with a purity ofat least 50%.
 9. The nutraceutical or therapeutic composition accordingto claim 2, wherein crocin and crocetin are extracted, enriched and/orpurified from natural source with a combined purity of at least 50%. 10.The nutraceutical or therapeutic composition according to claim 8,wherein the purity is at least 75%.
 11. The nutraceutical or therapeuticcomposition according to claim 8, wherein the purity is at least 90%.12. The nutraceutical or therapeutic composition according to claim 8,wherein the purity is at least 95%.
 13. The nutraceutical or therapeuticcomposition according to claim 8, wherein the purity is at least 99%.14. The nutraceutical or therapeutic composition according to claim 8,wherein the purity is at least 99.5%.
 15. The nutraceutical ortherapeutic composition according to claim 1, wherein crocin and/orcrocetin accounts for at least 1% by weight in the composition.
 16. Thenutraceutical or therapeutic composition according to claim 1, whereincrocin and/or crocetin accounts for at least 5% by weight in thecomposition.
 17. The nutraceutical or therapeutic composition accordingto claim 1, wherein crocin and/or crocetin accounts for at least 25% byweight in the composition.
 18. The nutraceutical or therapeuticcomposition according to claim 1, wherein crocin and/or crocetinaccounts for at least 99% by weight in the composition.
 19. Thenutraceutical or therapeutic composition according to claim 1, furthercomprising one or more ingredients selected from the following groups:(a) phytochemicals: acteoside, aloenin, aloesin, aloin, alpinetin,atractylenolide, atractylodin, aurantio-obtusin, arctigenin, arctiin,asiatic acid, asiaticoside, bergamotin, bergapten, betaine, dioscin,galangin, cimigenol, cimifugin, cimiside, garcinone, ascorbic acid,quercetin, resveratrol, pterostilbene, curcumin, demethoxycurcumin,bis-demethoxycurcumin, theaflavin, theaflavin-3,3′-digallate,theaflavin-3-gallate, theaflavin-3′-gallate, L-theanine, anthocyanidins,anthocyanins, catechin, epicatechin, gallocatechin, epigallocatechin,epicatechin gallate, gallocatechin gallate, epigallocatechin gallate,procyanidin, chlorogenic acid, cardamonin, cimicifugoside, cinnamicacid, ferrulic acid, fumaric acid, α-lipoic acid, carnosine,L-carnitine, caffeic acid, ellagic acid, maslinic acid, phenylethylcaffeate, caffeic acid phenethyl ester, theobromine, theophylline,caffeoylquinic acid, ursolic acid, allicin, gingerol, shogaol,ginkgolide, ginkgetin, ginsenoside, astragaloside, cycloastragenol,danshensu, danshenol, danshenxinkun, tanshinone, tanshindiol, rosmarinicacid, dosmin, nobiletin, tangeretin, luteolin, lutein, β-lycopene,zeaxanthin, tyrosol, hyperin, hyperoside, quercetrin, isoquercitrin,hydroxytyrosol, rosarin, β-rosasterol, rosavin, rosin, punicalagin,punicalin, myricetin, myricitrin, kaempferol, dihydromyricetin,apigenin, naringin, naringenin, honokiol, magnolol, mangiferin,mangostin, hesperetin, hesperidin, lupeol, indole-3-carbinol, genistein,genistin, daidzein, daidzin, cynarin, bilobalide, bilobetin, epimedin,sulforaphane, phloretin, phloretin-xyloglucoside, phloridzin,proanthocyanidins, procyanidin B1, procyanidin B2, procyanidin C1,silibinin, rutin, wogonin, morin, morusin, mulberroside A, mulberrosideB, glycyrrhizic acid, glycyrrhetinic acid, glycyrrhizic acid ammoniumsalt, linarin, protodioscin, protogracillin, synephrine, rebaudioside A,stevioside, vitexin, isovitexin, vitexin-4, vitexin-4″-O-glucoside,vitexin-2″-O-rhamnoside, vitexin-4′-rhamnoside, alpha-tocopherol,beta-tocopherol, gamma-tocopherol, delta-tocopherol; (b) amino acids orpeptides including the following: arginine, lysine, methionine,histedin, leucine, isoluceine, alanine, phenyalanine, asparingine,aspartic acid, tryptophane, proline, threonine, cysteine,selenocysteine, serine, taurine, tyrosine, valine, glycine, glutamine,glutamic acid, ornithine, carnosine, L-carnitine; (c) vitamins orminerals, including, but not limited to, vitamin A, vitamin C, vitaminB1, vitamin B2, vitamin 33, vitamin B6, vitamin B12, vitamin D, vitaminE, vitamin K (and derivatives), calcium, sodium, potassium, chromium,vanadium, magnesium, manganese, selenium, copper, molybdenum, boron,vanadium, and/or iron (and derivatives) (preferably in amounts less thanthe RDA); (d) natural food extracts that contain active phytochemicals,wherein the natural food extracts are selected from the group of appleextract, green tea extract, black tea extract, curcumin, bilberryextract, raspberry extract, blueberry extract, mulberry extract,pomegranate extract, cranberry extract, ginseng extract, ginger extract,goji extract, sea buckthorn extract, kudzu extract, clove extract, hempextract, cassia extract, magnolia extract, nutmeg extract, jujubeextract, honeysuckle extract, poria extract, grape extract, grape seedextract, ginkgo extract, garlic extract, garcinia extract, tomatoextract, coffee bean extract, olive extract, mango extract, bitter melonextract, bellflower extract, lotus extract, basil extract, sesameextract, angelica extract, cardamom extract, cinnamon extract,cimicifuga extract, epimedium extract, schisandra extract, salviaextract, turmeric extract, astragalus extract, aloe extract, rhodiolaextract, citrus fruit extract, orange extract, lemon extract, broccoliextract, licorice extract, artichoke leaf extract, dandelion extract,hawthorn extract, dodder extract, fenugreek extract, gotu kola extract,purslane extract, tribulus extract, stevia extract, lo han extract, hopsextract and mint extract, wherein the composition having the ingredientsin amount, individually and/or combined, to provide a therapeuticallysignificant benefit to prevent or treat diseases/conditions.
 20. Thenutraceutical or therapeutic composition according to claim 1, furthercomprising at least one ingredient selected from each of the followinggroups: (a) phytochemicals including the following: acteoside, aloenin,aloesin, aloin, alpinetin, atractylenolide, atractylodin,aurantio-obtusin, arctigenin, arctiin, asiatic acid, asiaticoside,bergamotin, bergapten, betaine, dioscin, galangin, cimigenol, cimifugin,cimiside, garcinone, ascorbic acid, astragalin, quercetin, resveratrol,pterostilbene, curcumin, demethoxycurcumin, bis-demethoxycurcumin,theaflavin, theaflavin-3,3′-digallate, theaflavin-3-gallate,theaflavin-3′-gallate, L-theanine, anthocyanidins, anthocyanins,catechin, epicatechin, gallocatechin, epigallocatechin, epicatechingallate, gallocatechin gallate, epigallocatechin gallate, procyanidin,chlorogenic acid, cardamonin, cimicifugoside, cinnamic acid, ferrulicacid, fumaric acid, α-lipoic acid, carnosine, L-carnitine, caffeic acid,ellagic acid, maslinic acid, phenylethyl caffeate, caffeic acidphenethyl ester, theobromine, theophylline, caffeoylquinic acid, ursolicacid, allicin, gingerol, shogaol, ginkgolide, ginkgetin, ginsenoside,astragaloside, cycloastragenol, danshensu, danshenol, danshenxinkun,tanshinone, tanshindiol, rosmarinic acid, dosmin, nobiletin, tangeretin,luteolin, lutein, β-lycopene, zeaxanthin, tyrosol, hyperin, hyperoside,quercetin, quercetrin, isoquercitrin, hydroxytyrosol, rosarin,β-rosasterol, rosavin, rosin, punicalagin, punicalin, myricetin,myricitrin, kaempferol, dihydromyricetin, apigenin, naringin,naringenin, honokiol, magnolol, mangiferin, mangostin, hesperetin,hesperidin, lupeol, indole-3-carbinol, genistein, genistin, daidzein,daidzin, cynarin, bilobalide, bilobetin, epimedin, sulforaphane,phloretin, phloretin-xyloglucoside, phloridzin, proanthocyanidins,procyanidin B1, procyanidin B2, procyanidin C1, silibinin, rutin,wogonin, morin, morusin, mulberroside A, mulberroside B, glycyrrhizicacid, glycyrrhizic acid ammonium salt, glycyrrhetinic acid, linarin,protodioscin, protogracillin, synephrine, rebaudioside A, stevioside,vitexin, isovitexin, vitexin-4, vitexin-4″-O-glucoside,vitexin-2″-O-rhamnoside, vitexin-4′-rhamnoside, alpha-tocopherol,beta-tocopherol, gamma-tocopherol, delta-tocopherol; (b) amino acids orpeptides including the following: arginine, lysine, methionine,histedin, leucine, isoluceine, alanine, phenyalanine, asparingine,aspartic acid, tryptophane, proline, threonine, cysteine,selenocysteine, serine, taurine, tyrosine, valine, glycine, glutamine,glutamic acid, ornithine, carnosine, L-carnitine; (c) vitamins orminerals, including, but not limited to, vitamin A, vitamin C, vitaminB1, vitamin B2, vitamin 33, vitamin B6, vitamin B12, vitamin D, vitaminE, vitamin K (and derivatives), calcium, sodium, potassium, chromium,vanadium, magnesium, manganese, selenium, copper, molybdenum, boron,vanadium, and/or iron (and derivatives) (preferably in amounts less thanthe RDA); (d) natural food extracts that contain active phytochemicals,wherein the natural food extracts are selected from the group of appleextract, green tea extract, black tea extract, curcumin, bilberryextract, raspberry extract, blueberry extract, mulberry extract,pomegranate extract, cranberry extract, ginseng extract, ginger extract,goji extract, sea buckthorn extract, kudzu extract, clove extract, hempextract, cassia extract, magnolia extract, nutmeg extract, jujubeextract, honeysuckle extract, poria extract, grape extract, grape seedextract, ginkgo extract, garlic extract, garcinia extract, tomatoextract, coffee bean extract, olive extract, mango extract, bitter melonextract, bellflower extract, lotus extract, basil extract, sesameextract, angelica extract, cardamom extract, cinnamon extract,cimicifuga extract, epimedium extract, schisandra extract, salviaextract, turmeric extract, astragalus extract, aloe extract, rhodiolaextract, citrus fruit extract, orange extract, lemon extract, broccoliextract, licorice extract, artichoke leaf extract, dandelion extract,hawthorn extract, lo han extract, dodder extract, fenugreek extract,gotu kola extract, purslane extract, tribulus extract, stevia extract,hops extract and mint extract, wherein the composition having theingredients in amount, individually and/or combined, to provide atherapeutically significant benefit to prevent or treatdiseases/conditions.
 21. The nutraceutical or therapeutic compositionaccording to claim 1, further comprising at least one of the following:a food or pharmaceutically acceptable carrier, excipient, stabilizer,and hydrotropes.
 22. The nutraceutical or therapeutic compositionaccording to claim 1, wherein said composition comprises, in percentageby weight, 1-60% of crocin or crocetin or both, 1-50% of green teaextract, 1-40% of curcumin, 1-40% of resveratrol, 1-40% of Panax ginsengextract, 0.5-20% of α-lipoic acid, and 0.1-20% of L-carnitine.
 23. Thenutraceutical or therapeutic composition according to claim 1, whereinsaid composition comprises, in percentage by weight, 1-50% of crocin orcrocetin or both, 10-75% of dihydromyricetin, 0.5-20% of resveratrol,0.5-20% of artichoke leaf extract (with 10-30% of chlorogenic acid and1-10% of cynarin).
 24. The nutraceutical or therapeutic compositionaccording to claim 1, wherein said composition comprising, in percentageby weight, 10-60% of citric acid, 5-40% of potassium bicarbonate, 5-40%of sodium bicarbonate, 0.5-20% of sodium carbonate, 0.5-30% of crocinsor crocetin or both, 0.2-10% of polyethylene glycol, 0.1-8% ofaspartame, 0.1-5% of flavorant, wherein the ingredients of thecomposition are blended and pressed into appropriate size ofeffervescent tablets.
 25. The nutraceutical or therapeutic compositionaccording to claim 1, wherein said composition in a porous lyophilizedform comprising, in percentage by weight, 10-99% of crocin or crocetinor both, and wherein the composition is capable of being readilyreconstituted into an injectable solution, or suspension or emulsion bymixing with water or saline or 5% dextrose solution or 5% glucosesolution or cyclodextrin or combination thereof using mild agitationthat does not require machine processing.
 26. The composition accordingto claim 1, wherein the composition is formed as tablets, soft gels,capsules, pills, caplets, dragees, granules, powders, or effervescenttablets, liquid, sprays, functional foods, gums, chewing gum, gummicandy, taffy, caramel candy, fudge, degradable thin films, nondegradablethin films, hard candy, liquids, drinks, or beverages.
 27. Thecomposition according to claim 1, wherein the composition is animmediate release composition, a mixed-release composition, or anenterically-coated composition.
 28. The composition according to claim27, wherein the mixed-release composition is a bilayer tablet.
 29. Thecomposition according to claim 1, wherein the composition is formed asan injectable.
 30. A method of enriching or purifying natural crocinand/or crocetin, comprising: (a) dissolving saffron, gardenia fruits,and/or gardenia yellow in 40-99% ethanol at temperature range from 10°C. to 70° C.; (b) filtration, crystallization and re-crystallization attemperature range from −20° C. to 4° C., followed by filtration, ifnecessary; (c) purification/separation by column chromatography,elution, concentration and drying to obtain enriched and/or purifiednatural crocin and/or crocetin.
 31. The method according to claim 30,wherein: in step (a), dissolving saffron, gardenia fruits, and/orgardenia yellow in 60-90% ethanol at temperature range from 30° C. to60° C.; and in step (b), the temperature range is from −10° C. to 0° C.32. A method of using the nutraceutical or therapeutic composition ofclaim 1, comprising administering said composition to a subject.
 33. Themethod according to claim 32, wherein said subject is a mammal.
 34. Themethod according to claim 33, wherein said subject is a human.
 35. Themethod according to claim 32, wherein said subject has at least onedisease/condition selected from the following: any cancer, aneurodegenerative disease/condition, a heart disease/condition, a liverdisease/condition, a kidney disease/condition, memory loss, mentalconfusion, metabolic syndrome, atherosclerosis, inflammation, obesity,diabetes;
 36. The method according to claim 32, wherein said subject hasat least one disease/condition selected from the following: lung cancer,liver cancer, breast cancer, colon cancer, colorectal cancer, pancreaticcancer, bladder cancer, stomach cancer, kidney cancer, gastrointestinalcancer, adrenal cancer, cervical cancer, prostate cancer, brain cancers,brain tumors, ovarian cancer, skin cancer, head cancer, neck cancer, eyeor ocular cancer, rectal cancer, anal cancer, bladder cancer, esophaguscancer, gallbladder cancer, bone cancer, endometrial cancer, nasalcavity and paranasal sinus cancer, nasopharyngeal cancer penile cancer,leukemia, lymphoma of the skin, carcinomas, kaposi sarcoma, sarcomas,lung carcinoid tumor, non-small cell lung cancer, salivary gland cancer,oral cavity and oropharyngeal cancer, bile duct cancer, small intestinecancer, testicular cancer, thymus cancer, thyroid cancer, vaginalcancer, vulvar cancer, aplastic anemia, castleman disease, Ewing familyof tumors, gastrointestinal carcinoid tumors, gastrointestinal stromaltumor (GIST), gestational trophoblastic disease, laryngeal andhypopharyngeal cancer, malignant mesothelioma, multiple myeloma,myelodysplastic syndrome, neuroblastoma, Hodgkin disease, non-Hodgkinlymphoma, osteosarcoma, pituitary tumors, retinoblastoma,rhabdomyosarcoma, uterine sarcoma, Waldenstrom macroglobulinemia, Wilmstumor, and any age-related cancer.
 37. The method according to claim 32,wherein said composition protects/improves/enhances thefunction/condition of at least one of the following: liver, kidney,heart, lung, eye, brain, skin, pancreas, stomach, esophagus, prostate,breast, ovarian, rectum, colon, bladder, and/or any other organ.
 38. Themethod according to claim 32, said administering is done through atleast one of the following: orally, transmucosally, buccally,percutaneously.
 39. The method according to claim 32, said administeringcomprising administering said composition parenterally via at least oneof the following: intravenous, intramuscular, intraperitoneal,intrasternal, subcutaneous, intraarticular injection, infusion.
 40. Themethod according to claim 32, said administering comprisingadministering said composition topically as powders, ointments, creams,sprays, drops or patches.
 41. The method according to claim 32, whereinsaid composition is administered through at least one of the following:rectal, mucosal, intranasal administration.
 42. The method according toclaim 32, wherein said composition is administered through ear drops,eye solutions, or eye ointments.
 43. The method according to claim 32,wherein said composition improves/enhances/restores cells, tissues,organ functions of said subject, and/or improves/prolongs life span ofsaid subject.
 44. The method according to claim 36, wherein saidcomposition enhances therapeutic effectiveness of other cancer drugsthrough synergistic effects.
 45. The method according to claim 36,wherein said composition serves as sensitizer and/or enhancer of othercancer drugs, and/or reduces drug resistance.
 46. The method accordingto claim 36, wherein said composition protects non-cancerous or normalcells, tissues, organs and patients from injury, damage by otheranti-cancer agents, toxins, chemotherapeutic agents, and radiation. 47.The method according to claim 32, wherein said composition prevents,mitigates or treats one of the following: Alzheimer's disease,Parkinson's disease, any other neurodegenerative disorder/disease. 48.The method according to claim 32, wherein said composition inhibitsneourtoxins or prevents acetylcholine breakdown, and/or prevents toxicbeta-amyloid formation/aggregation.
 49. The method according to claim32, wherein said composition improves/enhances brain function, healthyaging and/or mental health.
 50. The method according to claim 32,wherein said composition improves/enhances learning, memory and/orcognitive abilities.
 51. The method according to claim 32, wherein saidcomposition reduces oxidative stress.
 52. The method according to claim32, wherein said composition reduces/prevents damage to the hippocampusinduced by chronic stress.
 53. The method according to claim 32, whereinsaid composition prevents/treats alcohol-induced impairments oflearning, memory and/or cognitive abilities, and/or prevents/treatsneurodegenerative disorders.
 54. The method according to claim 37,wherein said composition protects/improves/enhances heartfunction/health by one of the following: improves antioxidant system,prevents/treats cardiac arrhythmia, prevents/treats myocardialinfarction, relieves myocardial stunning.
 55. The method according toclaim 32, wherein said composition reduces chronic inflammation, and/orprevents/treats inflammatory conditions.
 56. The method according toclaim 37, wherein said composition protects/improves/enhances thefunction/condition of liver, wherein said composition protects/preventsor treats liver injury from alcohols, toxins, shock, over dose of metalor heavy metal, and/or protects liver from chemo agent injury anddamage.
 57. The method according to claim 37, wherein said compositionprotects/improves/enhances the function/condition of kidney by at leastone of the following: protecting kidney from diseases and/or injury,preventing or treating kidney diseases and injury.
 58. The methodaccording to claim 32, wherein said composition improves and enhancesimmune system.
 59. The method according to claim 32, wherein saidcomposition has at least one of the following functions:slows/prevents/treats age-related macular degeneration, increases bloodflow to the retina and choroid, facilitates retinal function recoverythereby preventing ischemic retinopathy and age related maculardegeneration, and/or improves/enhances eye health or treat eyeconditions and diseases.
 60. The method according to claim 32, whereinsaid composition enhances/improves human circulation system by reducinglevel of cholesterol, triglyceride and low density lipoprotein.
 61. Themethod according to claim 32, wherein said compositionreduces/prevents/treats atherosclerosis.
 62. The method according toclaim 32, wherein said composition prevents/treats coronary arterydiseases, cardiovascular diseases and peripheral vascular diseases. 63.The method according to claim 32, wherein said compositionrestores/maintains normal pancreatic functions/orders, and/or preventsor treats glucose toxicity, insulin resistance or insensitivity.
 64. Themethod according to claim 32, wherein said composition prevents ortreats diabetes.
 65. The method according to claim 32, wherein saidcomposition prevents or treats overweight or obese.
 66. The methodaccording to claim 32, wherein said composition prevents or treatsdepression, and/or improves/enhances well-being.
 67. The methodaccording to claim 32, wherein said composition improves/enhances skinhealth, conditions and/or appearance.
 68. The method according to claim32, wherein said composition prevents/treats skin damage, ordelays/inhibits signs of skin aging through anti-aging, anti-wrinkle,anti-inflammation and/or anti-oxidation.
 69. The method according toclaim 32, wherein said composition improves or treats peripheralneuropathy, muscle pain, muscle cramping, joint pain and combinationsthereof.
 70. The method according to claim 36, wherein saidadministering is in conjunction with a cancer drug.
 71. The methodaccording to claim 60, wherein said administering is in conjunction witha cholesterol lowering drug.
 72. The method according to claim 36,wherein said administering is in conjunction with, prior to, and/orafter radiotherapy.
 73. The method according to claim 32, wherein saidcomposition is administered as a functional food product.
 74. The methodaccording to claim 73, which said functional food product comprises oneof the following: yogurt, sausage, sauce, cake, pie, soup, juice, icecream, drink, energy drink, beverage, or soda.